M1279 Overlapped Heartburn/Regurgitation Amplifies Abdominal Pain and Indigestion via Common Central Serotonin Neurotransmission Disorders in Patients With Functional Dyspepsia

Abstract

Background: Patients with functional dyspepsia (FD) tend to be more depressed and anxious than healthy controls but what comes first is not clear. We hypothesized that psychological morbidity can be secondary to abnormal gastrointestinal afferent signaling. We therefore evaluated depression-like and anxiety-like behaviors and the sensitivity to stress in a previously described rat model of FD. Methods: 10 days old male Sprague-Dawley rats received 0.2 ml of 0.1% iodoacetamide (IA) in 2% sucrose daily by oral gavages for 6 days. Control group received 2% sucrose. At 8-10 weeks of age, sucrose preference test (SPT) and forcedswim test (FST) were used for testing depression-like behavior and elevated plus maze (EPM) and open field test (OFT) were used to test anxiety-like behaviors. Subsequently plasma ACTH, corticosterone and oxytocin levels in response to a minor stressor (subcutaneous saline injection) were measured. RNA was extracted from various brain regions. Results: Rats with neonatal gastric irritation (NGI) showed several abnormalities on the FST as compared with control (Immobility: 32.4± 3.95 vs. 12.95±2.80, climbing: 7.05± 1.18 vs. 18.65 ±1.9 and swimming: 20.6± 3.02 vs. 28.35± 2.1, P 75% of total intake) was decreased in NGI rats (45% versus 80%; p <0.05). No significant change between NGI and control animals was observed in EPM test. On the other hand, OFT showed that the time at center and total distance moved were significantly decreased in NGI rats compared to control rats (16± 4. vs 30±5 and 9182±655 vs 11548± 332, P <0.05). The basal level of plasma corticosterone in NGI rats was significantly higher than that in control rats (3.05±0.74 vs. 1.41±0.25, P<0.05) although stress did not induce a further elevation. Further, while stress did not alter the plasma ACTH and oxytocin concentration in control rats, the hormone levels were significantly increased in stressed NGI rats compared to non-stressed FD rats (49.45±11.42 vs 22.76±2.05 and 14.87±1.50 vs 7.07±0.62, P<0.05). Gene array data showed significant changes in key molecules that modulate stress and depression including 5-HT1A, 5-HT2A, TrkB, NPYr1 and oxytocin. Conclusions: These results suggest that transient gastric irritation in the neonatal period can induce long lasting depressive behavior as well as sensitivity to stress, associated with specific molecular correlates. These findings have major implications for the pathogenesis and treatment of psychological co-morbidity in patients with FD. Thus, gastric hypersensitivity could be a cause rather than an effect of depression.